Tricuspid regurgitation following pacemaker implantation for bradycardia: a two-year study comparing different pacing strategies

To the Editor: Tricuspid regurgitation (TR) is a known complication of cardiac implantable electrical device (CIED) implantation with a prevalence of up to 10–30%. Due to the detrimental effects of right ventricular pacing (RVP) on cardiac function, His bundle pacing (HBP) and left bundle branch area pacing (LBBAP) have been increasingly used as physiological pacing modalities. This observational study aimed to assess the lead-related significant TR (moderate and severe) in patients with HBP, LBBAP, right ventricular apical pacing (RVAP), and right ventricular septal pacing (RVSP) in bradycardia patients during the two-year follow-up. All consecutive patients with left ventricular ejection fraction (LVEF) over 40% who received pacemaker implantation due to bradycardia were enrolled if they underwent successful HBP or LBBAP or RVP from October 2018 to December 2020 in Fuwai Hospital. The pacing modality was decided by the two physicians who performed the implantation procedures. Patients were excluded for the final analysis if they received implantable cardioverter-defibrillator or biventricular pacing, or if they had a history of tricuspid annuloplasty. All patients signed written informed consent for an agreement of the implantation procedure and analysis of clinical data, and this study was approved by the Review Board of Fuwai Hospital (No. 2019-1223). Venous access was obtained via the left or right axillary or subclavian vein. LBBAP or HBP was performed using the 3830 lead (Select Secure system, Medtronic, Inc., Minneapolis, MN, USA). The procedure of HBP and LBBAP followed the previous descriptions.[1,2] The procedure of RVP followed a standard fashion by placing the ventricular lead at the RV apex or septum, and stylet-driven pacing leads were routinely used. All patients were followed every 6 months after pacemaker implantation. We collected the pacing parameters at the latest device follow up. Lead-related complications were routinely tracked. All patients underwent transthoracic echocardiography at baseline (1 or 2 days before the procedure) and during follow up by using Vivid E9 systems (GE Vingmed Ultrasound AS, Horten, Norway). Multiple echocardiographic views were evaluated to quantify TR and to assess if there was any limitation of tricuspid leaflet motion induced by the septal electrode. Grading of TR was identified based on the 2017 American Society of Echocardiography recommendations for valvular regurgitation.[3] In patients with LBBAP, the distance from the septal leaflet of the tricuspid valve (TV) to the electrode screwing site (electrode–tricuspid valve distance, E–T distance) was measured from a standard 4-chamber view. TR grade was interpreted by two experienced echocardiographers. In cases of disagreement, an invited echocardiographer examined the echocardiogram and reached an agreement on the grade. The primary endpoint for this study was the first occurrence of worsening of TR during follow up, which was defined as an increase in TR of at least one grade and the TR grade up to moderate or severe as compared with that at pre-implantation. Statistical analyses were performed with SPSS version 24.0 (SPSS, Inc., Chicago, IL, USA). Continuous variables were presented as the mean ± standard deviation (SD) and compared with analysis of variance (ANOVA) analysis. Nominal data were presented as numbers and percentages and were compared by chi-squared test. Kaplan–Meier survival methods were used to compare significant TR risk. Cox regression models for significant TR were used to assess the association between pacing strategies and risk of TR. Receiver operating characteristics (ROC) curves were used to determine the cut-off point of the best E–T distance. Two-tailed P-value of <0.05 was considered significant. During the study period, 608 consecutive patients who underwent permanent pacemaker implantation were finally enrolled (HBP, n = 44, LBBAP, n = 269, RVSP, n = 203, and RVAP, n = 92). Most clinical characteristics were comparable among the four groups, except for age, the prevalence of AVB, previous atrial fibrillation (AF), and percutaneous coronary intervention or coronary artery bypass grafting history. The prevalence of moderate TR at baseline was comparable among the four pacing groups. During the mean follow-up of 23.7 ± 4.8 months, significant TR progression differed significantly among four pacing groups (LBBAP 14.5% [39/269] vs. HBP 2.3% [1/44] vs. RVSP 5.9% [12/203] vs. RVAP 13.0% [12/92],χ2 = 12.898, P = 0.004). LBBAP demonstrated the highest risk of significant TR worsening as compared with other pacing modalities, while HBP had the lowest risk of significant TR progression. During the follow-up period, 4.3% (26/608) of the cohort's patients suffered heart failure hospitalization events (HBP 0% [0/44], LBBAP 1.9% [5/269], RVSP 5.9% [12/203], RVAP 9.8% [9/92], χ2 = 13.946,P = 0.003), and no all-cause death events occurred. Two patients who received LBBAP suffered from perioperative septal perforation and received acute lead revision, and two patients in HBP experienced increased pacing threshold (increment of pacing threshold ≥1.0 V/0.4 ms) during the follow up and the pulse width of 1.0 ms was programmed. One of the patients in the RVAP group suffered chronic perforation and received late lead adjustment at a 3-month follow up. The univariate and multivariate analyses of risk factors of post-procedure significant TR worsening are shown in Table 1. When compared with RVP (including RVAP and RVSP), LBBAP conferred a 2.59-fold increased risk of significant TR worsening after adjustment for multiple clinical factors. HBP did not demonstrate a statistically significant decrease in the significant TR worsening risk. VP >40% was also an independent risk factor of significant TR worsening after pacemaker implantation in the whole study population. Table 1 - Univariate and multivariate analyses for the progression of TR in the overall cohort and LBBAP cohort. Variables Univariate analysis Multivariate analysis Hazard ratio (95% CI) P-value Hazard ratio (95% CI) P-value Overall cohort Pacing strategies HBP vs. RVP 0.25 (0.04–1.90) 0.183 0.24 (0.03–1.80) 0.164 LBBAP vs. RVP 3.06 (1.83–5.13) <0.001 2.59 (1.51–4.44) 0.001 Age (years) 1.02 (1.00–1.04) 0.049 1.12 (0.99–1.04) 0.156 Female 1.64 (1.00–2.69) 0.048 1.63 (0.98–2.69) 0.058 Atrial fibrillation 1.66 (1.01–2.73) 0.045 1.60 (0.96–2.67) 0.072 Ventricular pacing >40% 2.06 (1.18–3.58) 0.011 2.06 (1.15–3.70) 0.016 MI or coronary intervention 2.24 (1.22–4.13) 0.008 1.91 (0.99–3.68) 0.053 Operator 0.82 (0.60–1.11) 0.202 Baseline tricuspid regurgitation 0.80 (0.49–1.32) 0.380 LBBAP cohort Age (years) 1.02 (0.99–1.06) 0.196 1.00 (0.97–1.04) 0.948 Female 1.78 (0.79–3.97) 0.152 1.23 (0.52–2.91) 0.630 Atrial fibrillation 4.68 (2.12–10.33) <0.001 6.04 (2.50–14.60) <0.001 Ventricular pacing >40% 0.51 (0.23–1.10) 0.091 0.53 (0.21–1.39) 0.197 Previous MI or coronary intervention 1.64 (0.48–5.53) 0.457 Operator 0.75 (0.41–1.40) 0.336 Baseline tricuspid regurgitation 0.67 (0.36–1.25) 0.203 Distance from the base of TV leaflet 0.86 (0.76–0.97) 0.009 0.77 (0.68–0.91) 0.002 AF: Atrial fibrillation; CI: Confidence interval; HBP: His bundle pacing; LBBAP: Left bundle branch area pacing; MI: Myocardial infarction; RVP: Right ventricular pacing; TR: Tricuspid regurgitation; TV: Tricuspid valve. Compared with patients without significant worsening of TR, those with significant worsening of TR had a higher predicted prevalence of AF (50.0% vs. 24.9%, log-rank χ² = 9.952, P = 0.002) and a shorter E–T distance (20.2 ± 2.6 mm vs. 22.3 ± 2.6 mm, t value = 2.463, P = 0.010). Other clinical characteristics were comparable between patients with and without significantly worsening TR. As shown in Table 1, after adjustment of age, gender, VP >40%, and previous myocardial infarction or coronary disease history, the increased risk of significant TR progression was independently associated with AF (hazard ratio [HR] 6.04, 95% confidence interval [CI]: 2.50–14.60, P <0.001) and the E–T distance (HR 0.77, 95% CI: 0.68–0.91, P = 0.002) in patients received LBBAP implantation. However, VP >40% was no longer the independent risk factor of significant TR worsening after pacemaker implantation in patients who received LBBAP. ROC curve analysis was used to find the best cut-off value of the E–T distance influencing the risk of significant post-procedure TR progression. According to the cut-off value of 20 mm E–T distance, patients with LBBAP were divided into proximal LBBAP (E–T distance <20 mm) and distal LBBAP groups (E–T distance ≥20 mm). Kaplan–Meier analysis showed that distal LBBAP was related to significantly decreased risk of significant post-procedure TR progression (18.6% vs. 61.4%; χ² = 7.713, P = 0.006 by Log-rank test) when compared with proximal LBBAP. Pacing parameters and paced QRS duration were comparable between proximal and distal LBBAP. The present study demonstrated the risk of significant TR progression in bradycardia patients with LBBAP and comparison among four pacing modalities: HBP, LBBAP, RVSP, and RVAP. Our study found that LBBAP was associated with an increased risk of significant TR as compared with RVP. The risk of LBBAP-related significant TR progression was negatively associated with the E–T distance in the RV septum. AF was the other factor associated with an increased risk of LBBAP-related significant TR progression. Four pacing approaches demonstrated a different association between pacing lead and TV. HBP-related TR progression is very rare due to the location of His bundle. In some patients with HBP, the pacing lead may be positioned on the atrial side. Therefore, the TV function mostly remains stable after the HBP procedure. In this study, the lowest TR progression was observed in the HBP group (2.3%) during follow up. The prevalence of significant TR progression in patients with RVP in our study was consistent with the previous results,[4] and RVSP demonstrated less prevalence of post-procedure significant TR worsening than RVAP in our study. The less TR progression risk in patients with RVSP may be caused by mild mechanical and electrical dyssynchrony and less lead-related interference as compared with RVAP. The association of LBBAP with significant TR progression has been focused on in this study. In previous studies, Vijayaraman et al[1] reported 7% (4/55) of TR progression in patients with LBBAP. In their study, the E–T distance was 22.0 mm on average, and they reported a moderate TR due to the impingement of the septal leaflet by the LBBAP lead (E–T distance 11 mm). Our results observed a negative association between E–T distance and TR progression. Therefore, we surmised that the short E–T distance might contribute to the occurrence of LBBAP-related significant TR progression. The higher risk of significant TR progression in patients with short E–T distance might be due to the mechanical TV interference. Recently, Su et al[5] reported the occurrence of TR worsening of 12.3% in their single-center experience of 560 patients with LBBAP after 1-year follow up. Our study identified a cut-off point of 20 mm of E–T distance and found that distal LBBAP (E–T distance ≥20 mm) was associated with decreased risk of significant TR progression. In patients with LBBAP, AF was a risk factor associated with LBBAP-related significant TR progression. AF can cause the enlarged right atrium and tricuspid annular dilation and diastolic dysfunction of LV. Our study observed the association between AF and significant TR progression in patients with LBBAP but not in the whole study population with four pacing forms. In contrast, high VP percentage was another risk factor of post-CIED TR progression in the whole study population but not in patients with LBBAP. We speculated that the impact of dyssynchrony on TR progression due to high VP percentage in patients with non-physiological RVP was reduced in patients with LBBAP, and then the impact of AF on TR progression appeared obviously. Several limitations in this study need to be mentioned. First, the non-randomized study design was the major limitation and our findings might be overstated due to the unrecognized confounders. Second, the sample size was not comparable among the four pacing modality groups, and HBP or RVAP group had a relatively small sample size. However, the incidence of significant TR worsening was consistent with previous studies. Third, the postoperative TR outcomes could be impacted by the pacing electrode selection and lead reserve length. Additionally, RV function was not routinely evaluated in this study, which will be focused in the future study. Overall, LBBAP might be associated with an increased risk of lead-related significant TR as compared with other pacing strategies based on the two-year follow-up results, and the E–T distance might influence the risk of LBBAP-related significant TR progression. The distal LBBAP (with E–T distance ≥20 mm) may achieve equal pacing efficacy to proximal LBBAP and confer a comparable risk of significant TR progression with RVP. Funding This work was supported by grants from the National Natural Science Foundation of China to Xiaohan Fan (No. 81970284), and the project for the Distinguishing Academic Discipline of Fuwai Hospital (No. 2022-FWQN16) to Xiaofei Li. Conflicts of interest None.